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951.
Claudia Bello Michele Cea Giovanna Dal Bello Anna Garuti Ilaria Rocco Gabriella Cirmena Eva Moran Aimable Nahimana Michel A. Duchosal Floriana Fruscione Paolo Pronzato Francesco Grossi Franco Patrone Alberto Ballestrero Marc Dupuis Bernard Sordat Alessio Nencioni Pierre Vogel 《Bioorganic & medicinal chemistry》2010,18(9):3320-3334
Novel α-mannosidase inhibitors of the type (2R,3R,4S)-2-({[(1R)-2-hydroxy-1-arylethyl]amino}methyl)pyrrolidine-3,4-diol have been prepared and assayed for their anticancer activities. Compound 30 with the aryl group = 4-trifluoromethylbiphenyl inhibits the proliferation of primary cells and cell lines of different origins, irrespective of Bcl-2 expression levels, inducing a G2/Mcell cycle arrest and by modification of genes involved in cell cycle progression and survival. 相似文献
952.
Pierfrancesco Biagini Claudio Biancalani Alessia Graziano Nicoletta Cesari Maria Paola Giovannoni Agostino Cilibrizzi Vittorio Dal Piaz Claudia Vergelli Letizia Crocetti Maurizio Delcanale Elisabetta Armani Andrea Rizzi Paola Puccini Paola Maria Gallo Daniele Spinabelli Paola Caruso 《Bioorganic & medicinal chemistry》2010,18(10):3506-3517
A series of pyrazoles and pyrazolo[3,4-d]pyridazinones were synthesized and evaluated for their PDE4 inhibitory activity. All the pyrazoles were found devoid of activity, whereas some of the novel pyrazolo[3,4-d]pyridazinones showed good activity as PDE4 inhibitors. The most potent compounds in this series showed an IC50 in the nanomolar range. The ability to inhibit TNF-α release in human PBMCs was determined for two representative compounds, finding values in the sub-micromolar range. SARs studies demonstrated that the best arranged groups around the heterocyclic core are 2-chloro-, 2-methyl- and 3-nitrophenyl at position 2, an ethyl ester at position 4 and a small alkyl group at position 6. Molecular modeling studies performed on a representative compound allowed to define its binding mode to the PDE4B isoform. 相似文献
953.
954.
Raffaele Saladino Veronica Neri Claudia Crestini Giovanna Costanzo Michele Graciotti Ernesto Di Mauro 《Journal of molecular evolution》2010,71(2):100-110
We describe the one-pot synthesis of a large variety of nucleic acid bases and related compounds from formamide in the presence
of zirconium minerals as catalysts. The major products observed are: purine, 2-hydroxy pyrimidine, 5-hydroxy pyrimidine, isocytosine,
adenine, urea, and carbodiimide. The synthesis of low molecular weight amides and carboxylic acid derivatives (intermediates
of extant metabolism) was also observed: glyoxylamide, glycolic-, lactic-, succinic-, oxalic-, fumaric-, and maleic acids.
As the major problem in the origin of informational polymers is the instability of their precursors, we also investigated
the effects of zirconia minerals on the stability of ribooligonucleotides in formamide and in water. The relevance of these
findings with respect to the origin of informational polymers and primordial metabolism is discussed. 相似文献
955.
Patricia L. Fernandez Fabianno F. Dutra Letícia Alves Rodrigo T. Figueiredo Diego Mour?o-Sa Guilherme B. Fortes Sophie Bergstrand David L?nn Ricardo R. Cevallos Renata M. S. Pereira Ulisses G. Lopes Leonardo H. Travassos Claudia N. Paiva Marcelo T. Bozza 《The Journal of biological chemistry》2010,285(43):32844-32851
Infectious diseases that cause hemolysis are among the most threatening human diseases, because of severity and/or global distribution. In these conditions, hemeproteins and heme are released, but whether heme affects the inflammatory response to microorganism molecules remains to be characterized. Here, we show that heme increased the lethality and cytokine secretion induced by LPS in vivo and enhanced the secretion of cytokines by macrophages stimulated with various agonists of innate immune receptors. Activation of nuclear factor κB (NF-κB) and MAPKs and the generation of reactive oxygen species were essential to the increase in cytokine production induced by heme plus LPS. This synergistic effect of heme and LPS was blocked by a selective inhibitor of spleen tyrosine kinase (Syk) and was abrogated in dendritic cells deficient in Syk. Moreover, inhibition of Syk and the downstream molecules PKC and PI3K reduced the reactive oxygen species generation by heme. Our results highlight a mechanism by which heme amplifies the secretion of cytokines triggered by microbial molecule activation and indicates possible pathways for therapeutic intervention during hemolytic infectious diseases. 相似文献
956.
Antonio Porro Michelle Haber Daniel Diolaiti Nunzio Iraci Michelle Henderson Samuele Gherardi Emanuele Valli Marcia A. Munoz Chengyuan Xue Claudia Flemming Manfred Schwab Jason H. Wong Glenn M. Marshall Giuliano Della Valle Murray D. Norris Giovanni Perini 《The Journal of biological chemistry》2010,285(25):19532-19543
957.
Michael G. Kozoriz John Church Mark A. Ozog Christian C. Naus Claudia Krebs 《The Journal of biological chemistry》2010,285(41):31107-31119
Increases in extracellular potassium concentration ([K+]o), which can occur during neuronal activity and under pathological conditions such as ischemia, lead to a variety of potentially detrimental effects on neuronal function. Although astrocytes are known to contribute to the clearance of excess K+o, the mechanisms are not fully understood. We examined the potential role of mitochondria in sequestering K+ in astrocytes. Astrocytes were loaded with the fluorescent K+ indicator PBFI and release of K+ from mitochondria into the cytoplasm was examined after uncoupling the mitochondrial membrane potential with carbonyl cyanide m-chlorophenylhydrazone (CCCP). Under the experimental conditions employed, transient applications of elevated [K+]o led to increases in K+ within mitochondria, as assessed by increases in the magnitudes of cytoplasmic [K+] ([K+]i) transients evoked by brief exposures to CCCP. When mitochondrial K+ sequestration was impaired by prolonged application of CCCP, there was a robust increase in [K+]i upon exposure to elevated [K+]o. Blockade of plasmalemmal K+ uptake routes by ouabain, Ba2+, or a mixture of voltage-activated K+ channel inhibitors reduced K+ uptake into mitochondria. Also, reductions in mitochondrial K+ uptake occurred in the presence of mito-KATP channel inhibitors. Rises in [K+]i evoked by brief applications of CCCP following exposure to high [K+]o were also reduced by gap junction blockers and in astrocytes isolated from connexin43-null mice, suggesting that connexins also play a role in K+ uptake into astrocyte mitochondria. We conclude that mitochondria play a key role in K+o handling by astrocytes. 相似文献
958.
959.
Dorthe Helena Larsen Catherine Poinsignon Thorkell Gudjonsson Christoffel Dinant Mark R. Payne Flurina J. Hari Jannie M. Rendtlew Danielsen Patrice Menard Jette Christensen Sand Manuel Stucki Claudia Lukas Jiri Bartek Jens S. Andersen Jiri Lukas 《The Journal of cell biology》2010,190(5):731-740
In response to ionizing radiation (IR), cells delay cell cycle progression and activate DNA repair. Both processes are vital for genome integrity, but the mechanisms involved in their coordination are not fully understood. In a mass spectrometry screen, we identified the adenosine triphosphate–dependent chromatin-remodeling protein CHD4 (chromodomain helicase DNA-binding protein 4) as a factor that becomes transiently immobilized on chromatin after IR. Knockdown of CHD4 triggers enhanced Cdc25A degradation and p21Cip1 accumulation, which lead to more pronounced cyclin-dependent kinase inhibition and extended cell cycle delay. At DNA double-strand breaks, depletion of CHD4 disrupts the chromatin response at the level of the RNF168 ubiquitin ligase, which in turn impairs local ubiquitylation and BRCA1 assembly. These cell cycle and chromatin defects are accompanied by elevated spontaneous and IR-induced DNA breakage, reduced efficiency of DNA repair, and decreased clonogenic survival. Thus, CHD4 emerges as a novel genome caretaker and a factor that facilitates both checkpoint signaling and repair events after DNA damage. 相似文献